1. Field of the Invention
This invention relates to methods for treating congestive heart failure, in particular by the administration to a human subject of an aliquot of modified blood, optionally in combination with one or more other treatments for alleviating the symptoms of congestive heart failure.
2. Description of the Prior Art
Congestive heart failure (CHF) is a relatively common disorder affecting approximately five million Americans, with a mortality rate of over 80,000 per year. It is believed that CHF is not a distinct disease process in itself, but rather represents the effect of multiple anatomic, functional and biologic abnormalities which interact together to ultimately produce progressive loss of the ability of the heart to fulfill its function as a circulatory pump.
CHF may be caused by the occurrence of an index event such as a myocardial infarction (heart attack) or be secondary to other causes such as hypertension or cardiac malformations such as valvular disease. The index event or other causes result in an initial decline in the pumping capacity of the heart, for example by damaging the heart muscle. This decline in pumping capacity may not be immediately noticeable, due to the activation of one or more compensatory mechanisms. However, the progression of CHF has been found to be independent of the patient""s hemodynamic status. Therefore, the damaging changes caused by the disease are present and ongoing even while the patient remains asymptomatic. In fact, the compensatory mechanisms which maintain normal cardiovascular function during the early phases of CHF may actually contribute to progression of the disease, for example by exerting deleterious effects on the heart and circulation.
Some of the more important pathophysiologic changes which occur in CHF are activation of the hypothalamic-pituitary-adrenal axis, systemic endothelial dysfunction and myocardial remodeling.
Therapies specifically directed at counteracting the activation of the hypothalamic-pituitary-adrenal axis include beta-adrenergic blocking agents (xcex2-blockers), angiotensin converting enzyme (ACE) inhibitors, certain calcium channel blockers, nitrates and endothelin-1 blocking agents. Calcium channel blockers and nitrates, while producing clinical improvement have not been clearly shown to prolong survival whereas xcex2-blockers and ACE inhibitors have been shown to significantly prolong life, as have aldosterone antagonists. Experimental studies using endothelin-1 blocking agents have shown a beneficial effect.
Systemic endothelial dysfunction is a well-recognized feature of CHF and is clearly present by the time signs of left ventricular dysfunction are present. Endothelial dysfunction is important with respect to the intimate relationship of the myocardial microcirculation with cardiac myocytes. The evidence suggests that microvascular dysfunction contributes significantly to myocyte dysfunction and the morphological changes which lead to progressive myocardial failure.
In terms of underlying pathophysiology, evidence suggests that endothelial dysfunction may be caused by a relative lack of NO which can be attributed to an increase in vascular O2xe2x88x92 formation by an NADH-dependent oxidase and subsequent excess scavenging of NO. Potential contributing factors to increased O2xe2x88x92 production include increased sympathetic tone, norepinephrine, angiotensin II, endothelin-1 and TNF-xcex1. In addition, levels of IL-10, a key anti-inflammatory cytokine, are inappropriately low in relation to TNF-xcex1 levels. It is now believed that elevated levels of TNF-xcex1, with associated proinflammatory cytokines including IL-6, and soluble TNF-xcex1 receptors, play a significant role in the evolution of CHF by causing decreased myocardial contractility, biventricular dilatation, and hypotension and are probably involved in endothelial activation and dysfunction. It is also believed that TNF-xcex1 may play a role in the hitherto unexplained muscular wasting which occurs in severe CHF patients. Preliminary studies in small numbers of patients with soluble TNF-receptor therapy have indicated improvements in NYHA functional classification and in patient well-being, as measured by quality of life indices.
Myocardial remodeling is a complex process which accompanies the transition from asymptomatic to symptomatic heart failure, and may be described as a series of adaptive changes within the myocardium. The main components of myocardial remodeling are alterations in myocyte biology, loss of myocytes by necrosis or apoptosis, alterations in the extracellular matrix and alterations in left ventricular chamber geometry. It is unclear whether myocardial remodeling is simply the end-organ response that occurs following years of exposure to the toxic effects of long-term neurohormonal stimulation, or whether myocardial remodeling contributes independently to the progression of heart failure. Evidence to date suggests that appropriate therapy can slow or halt progression of myocardial remodeling.
Although presently used treatments can alleviate symptoms of CHF and correct certain pathophysiologic abnormalities caused by the disease process, CHF remains a relentlessly progressive condition with a relatively high rate of mortality. In fact, relative reductions in morbidity and mortality brought about by existing drugs are on the order of about 10 to 25 percent. Therefore, the need exists for additive or superior treatments for CHF, especially those which can significantly modify the underlying disease.
The present invention overcomes at least some of the above-noted and other disadvantages of presently known CHF therapies by providing a method for treating CHF in which an aliquot of mammalian blood is treated ex vivo and subsequently introduced into the body of a mammalian subject.
The aliquot of blood is treated by being subjected to one or more stressors which have been found to modify the blood. According to the present invention, the blood aliquot can be modified by subjecting the blood, or separated cellular or non-cellular fractions of the blood, or mixtures of the separated cells and/or non-cellular fractions of the blood, to stressors selected from temperature stressors, electromagnetic emissions and oxidative environments, or any combination of such stressors, simultaneously or sequentially.
As discussed above, the pathophysiologic changes associated with CHF include immune activation, endothelial dysfunction and loss of myocytes through necrosis and/or apoptosis. The treatment method of the present invention has been shown to produce therapeutic benefits in each of these three areas.
With respect to immune activation, the treatment of the present invention has been found to modulate levels of inflammatory cytokines in several Th1/TNF-xcex1-dependent experimental Inflammatory models in different species. For example, the treatment has been shown to reduce allergic contact hypersensitivity in Balb/c mice, a Th1-driven immune reaction mediated by TNF-xcex1 (Shivji et al., Journal of Cutaneous Medicine and Surgery 4: 132-137, 2000); to down-regulate expression of IL-6 mRNA in adjuvant-induced arthritis in the Lewis rat model of inflammatory disease; and to decrease the proportion of Th1 to Th2 cells in patients with scleroderma, a Th1-driven autoimmune disease (Rabinovich et al., Poster presented at the XII Pan-American Congress of Rheumatology, Montreal, Canada, Jun. 21-25, 1998). It is believed that the treatment down-regulates the pro-inflammatory Th1-type immune response, for example by increasing anti-inflammatory TH2-type cytokines, including IL-10.
The treatment of the invention has been found to improve endothelial function in a number of studies conducted in humans and in animals. For example, the treatment has been found to improve endothelial-dependent vasodilator function in an open study on patients with severe primary Raynaud""s disease (Cooke et al., International Journal of Angiology 16: 250-254, 1997), to improve the rate of recovery of skin blood flow following temporary occlusion in a double-blind, placebo-controlled study in patients with advanced peripheral vascular disease secondary to atherosclerosis (Courtman et al., Circulation Vol 102, #18, suppl II, 2000), to reduce progression of atherosclerosis in the cholesterol-fed LDL receptor deficient mouse (Babaei et al., Journal of the American College of Cardiology 35 (Suppl. A): 243, 1999), and to markedly improve endothelial-dependent vasodilator function to acetylcholine in severely atherosclerotic, hypercholesterolemic Watanabe rabbits as evidenced by an increased vasodilatory response to the nitric oxide agonist (acetycholine) (Courtman et al., above). It is believed that the improvement in endothelial function is due to an anti-inflammatory effect and to increased availability of NO which may result in an improvement in vasodilatory capacity, known to be severely impaired in CHF patients.
With regard to myocyte loss, the method of the invention is believed to decrease levels of apoptosis and necrosis. It has been shown that the treatment can protect the kidney from ischemia/reperfusion (I/R) damage known to be associated with increased apoptotic cell death (Tremblay et al., Pathophysiology 5:26; Chen et al., Medecine Sciences 15 (Suppl. 1): 16), and can reduce apoptosis in the kidney following I/R as determined by DNA laddering and density of apoptotic nuclei stained by Tdt.
Because the treatment of the invention produces therapeutic benefits in three areas in which pathophysiologic changes occur in CHF, namely endothelial dysfunction, production of inflammatory cytokines and myocyte loss due to apoptosis, there is provided a strong theoretical basis on which to predict that the treatment of the invention would be beneficial to patients with CHF. The method of the invention may be used as a CHF therapy on its own or in combination with other therapies, such as nitrate therapy, xcex2-blockers, ACE inhibitors, AT receptor blocking agents, aldosterone antagonists, calcium channel blocking agents, TNF blocking agents, suppressors of production of TNF-xcex1, and/or other more routine treatment measures such as sodium and fluid restriction, diuretics, digitalis, etc. Specific drugs known to suppress TNF-xcex1 production include pentoxifylline, amrinone, adenosine, thalidomide, TNF converting enzyme (TACE) inhibitors and dexamethasone. Specific TNF blocking agents include monoclonal antibodies and etanercept.
Accordingly, in one aspect the present invention provides a method of treating CHF in a human patient suffering therefrom, comprising: (a) treating an aliquot of the patient""s blood ex vivo with at least one stressor selected from the group consisting of a temperature above or below body temperature, an electromagnetic emission and an oxidative environment; and (b) administering the aliquot of blood treated in step (a) to the patient, wherein the aliquot has a volume sufficient to alleviate CHF in the patient.
In another aspect, the present invention provides a combination treatment for CHF in a human patient suffering therefrom, the combination treatment including the administration to the patient of an aliquot of the patient""s own blood which has been treated ex vivo with one or more stressors selected from an oxidative environment, thermal stress and electromagnetic emission, and a treatment selected from the group consisting of nitrates, xcex2-blockers, ACE inhibitors, AT receptor blocking agents, aldosterone antagonists, calcium channel blocking agents, TNF blocking agents, suppressors of production of TNF-xcex1, sodium and fluid restriction, diuretics and digitalis.